Biomedical subjects
Publications and source records attributed to R Heywood.
The i.v administration of lentinan to the Beagle dog induced changes in the cytoplasm of macrophagic cells in the liver, spleen, kidney, lungs, lymph nodes, small intestine. Electron-lucent or filamentous inclusions were demonstrated in the liver, kidney and spleen. A dose level of 0.5 mg/kg/day was without adverse effect.
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Five rhesus monkeys were treated with levonorgestrel-releasing intravaginal rings for 52 weeks. The rings were designed to provide a sustained release of ten times the human dose level of the hormone. Histological examination of the uterine endometrium showed widespread decidualisation of endometrial stromal cells. Ultrastructurally, two distinct cell types were identified: decidual and granular. Some of the decidual cells were ultrastructurally comparable with those reported elsewhere; however, in aproportion of these cells, intracisternal sequestration of the rough endoplasmic reticulum was widespread. The granular cells resembled those described in the metrial gland of rats and, as their name suggests, contained variable numbers of electron-dense granules.
Acute single overdosage (1.0 mg/kg, i.m.) with the novel benzmorphan narcotic analgesic agent Cogazocine lactate lowered serum LH and testosterone concentrations of Beagle dogs. The effect was rapidly reversible and persisted for less than 24 h after drug administration. Repeated administration (1.0 mg/kg, i.m.) induced reversible suppression of spermatid maturation with subsequent effects on semen characteristics. Examination of circulating LH and testosterone concentrations, together with pituitary and prostate morphology, suggested that the changes were due to inhibition of LH release. It is probable that the underlying mechanism is an exaggerated pharmacological response to repeated overdosage, common to many potent narcotic analgesic agents.
Hexachlorophene was administered orally, at subneurotoxic doses, to rats (5 mg/kg/day) and dogs (3 mg/kg/day) for 9 weeks: some of the rats and dogs were observed for a further 13 weeks. The serum concentrations of pituitary gonadotrophin and testosterone were unaffected in either species. No changes were induced in the testicular dimensions or semen characteristics of dogs and no macroscopic post mortem abnormalities, organ weight differences or lesions detectable by conventional light microscopy were found in their testes, pituitaries or secondary sex organs. A transient reduction in the number of germ cells counted in cross-sections of seminiferous tubules was seen in rats after 4 weeks treatment. After 9 weeks treatment, reduced spermatogonial counts were recorded in canine seminiferous tubules; in other respects spermatogenesis was proceeding normally. No delayed effects were apparent in eith species. It is concluded that repeated administration of hexachlorophene at subneurotoxic levels did not induce significant impairment of spermatogenesis in rats or dogs.
Castrated rats receiving aspirin at a dose level of 1000 mg/kg showed necrosis of the proximal convoluted tubules, similar to that seen in female rats, and the extent of this lesion was increased by oestrogen pre-treatment. Urinary gamma-glutamyl transpeptidase activity was a useful indicator of the necrotic changes induced.
Morphine sulphate was administered, buy s.c. injection, to male rats at 50 mg/kg/day for up to 9 weeks. Control rats were given s.c. injections of sterile water. Serum luteinising hormone (LH) and testosterone concentrations and the weight and morphology of testes, pituitary glands and secondary sex organs were examined after 4 and 9 weeks' morphine treatment and also 13 weeks after dosing stopped. Treatment with morphine decreased serum LH and testosterone concentrations and reduced secondary sex organ weights. Differential staining techniques revealed modified secretory activity of pituitary gonadotrophic cells. All stages of spermatogenesis were found in testicular sections, but quantitative reductions in spermatogenic cell populations were found among morphine-treated rats. All the observed effects were reversed within 13 weeks of drug withdrawal. These findings are discussed in relation to existing knowledge of the hormonal control of spermatogenesis in rats.
A quantitative histomorphometric assessment of testicular spermatogenesis was undertaken on testes from rats which had received 1-amino-3 chloro-2 propanol hydrochloride (CL 88, 236) at oral doses of 0, 50, 250 or 500 mg/kg/day for 12 weeks. Rats which developed epididymal sperm granulomata or severe atrophy of the germinal epithelium were excluded from quantitative examination. Pathological changes in the epididymis and semininferous epithelium were not strongly correlated. CL 88, 236 administered at 50 mg/kg/day was without effect on the histomorphometry of the seminiferous epithelium, although epididymal lesions occurred at this dose. At higher doses a quantitative reduction in testicular spermatids was evident. It appears important to differentiate between the selective antifertility action of CL 88, 236 on the biochemistry of epididymal spermatozoa and the disruption of epididymal physiology, and testicular spermatogenesis found at unusually high doses.
Dibekacin sulphate (DKB), a new aminoglycoside antibiotic developed on the theory of bacterial resistance, was given by intravenous injection to groups of female Beagle dogs at dosages of 2.5, 5.0, 10.0 or 25.0 mg/kg/day for 13 weeks. Physiological saline was given as a control. Some dogs given 5.0 or 10.0 mg/kg/day were retained undosed for a further 5 weeks in order to assess recovery. Premature deaths from acute renal tubular nephrosis occurred in dogs given 25.0 and 10.0 mg/kg/day. Dogs which survived treatment at 10.0 mg/kg/day showed marked elevation of circulating urea and creatinine concentrations after 4 weeks' treatment but thereafter the increases became less obvious. Varying degrees of renal cortical tubular dilatation, basophilia, degeneration or necrosis were seen in the kidneys of all dogs examined after 13 weeks treatment although no clinical impairment of renal function was detectable at dosages up to 5.0 mg/kg/day. These changes had essentially regressed in dogs examined 5 weeks after the last dose of DKB at 5.0 mg/kg/day. All the adverse clinical and histological effects noted, following any dose level of DKB tested, could be attributed to renal changes.
Semen samples were collected at weekly intervals for six weeks from eight sexually mature beagles previously shown to produce normal ejaculates. Seminal plasma and sperm fractions were separated by centrifugation and the sodium, potassium, alanine and aspartate aminotransferases, acid and alkaline phosphatase concentrations in the two fractions determined. Regression analysis of the mean weekly values obtained from physical and biochemical examination of the ejaculates showed that sodium ion concentration was highest in seminal plasma. The highest levels of aminotransferases were found in sperm fractions. Those enzymes may be indices of abnormal or damaged spermatozoa. Acid and alkaline phosphatase activity was 100 times greater in seminal plasma than in sperm fractions. Phosphatase concentrations are likely to be dependent on prostate activity. Measurement of acid phosphatase in canine semen therefore may be a useful index of prostate function. The motility of the semen samples was independent of the potassium concentration in seminal plasma. However, there was some evidence of a correlation between sperm motility and the enzyme and sodium content of seminal plasma.
The effects of levonorgestrel-loaded plastic intrauterine devices on endometrial morphology were investigated in 15 rhesus monkeys for 14 weeks. The devices were designed to release 25 microgram of the hormone per day and were inserted in the uterus by hysterotomy. Control animals were sham operated or received inert placebo devices. With the levonorgestrel-releasing devices, widespread changes in endometrial morphology were seen. These changes included atrophy of the endometrial mucosal and glandular epithelium and decidualization of the endometrial stroma. With the inert placebo control devices, only minor changes in endometrial morphology were observed.
The effects of levonorgestrel-releasing intravaginal rings were investigated in 15 rhesus monkeys for 52 weeks. The intravaginal rings were designed to provide a sustained release of either three or ten times the human dose level of the hormone. Untreated placebo rings were used as a control. The devices were well retained. After insertion of the vaginal rings, a dose-related decrease in vaginal bleeding was observed. The vaginal microbial flora were assessed qualitatively and semi-quantitatively and although all groups including controls showed some changes in microbial populations, by the end of the study nearly all animals returned to a normal balanced microflora. Terminal studies showed that, at the high dose level, ovulation was suppressed and widespread atrophy of the uterine mucosal and glandular epithelium had occurred. A dose-related increase in mucus within the lumen of the endocervical canal was observed. Focal or diffuse atrophy of the vaginal mucosal epithelium was seen in the majority of levonorgestrel-treated animals.
The effects of both progesterone- and norethisterone-loaded intravaginal rings were investigated in twenty-five rhesus monkeys for 52 weeks. The intravaginal rings were designed to provide a sustained release of either the human dosage level of the hormone or ten times this level. Untreated placebo rings were used for control purposes. The devices were well retained. With the exception of increased plasma fibrinogen levels in animals treated with norethisterone, no marked differences in either local or systemic toxicity between the progesterone and norethisterone intravaginal rings were apparent. Following insertion of the hormone-treated intravaginal rings, a dose-related decrease in vaginal bleeding was recorded. The vaginal microbial flora were assessed qualitatively and semiquantitatively and all groups including the placebo controls showed a changes in mcirobial populations. Terminal studies indicated that at high dose levels, ovulation was suppressed and widespread atrophy of the uterine mucosal and glandular endometrial epithelium had occurred. An increase in cervical mucus was observed within the lumen of the endocervical canal in a proportion of hormone-treated animals. In the vagina, a dose-related focal or diffuse atrophy of the mucosal epithelium was found.
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The paper presents results of experimental studies on a polybrominated flame retardant. Decabromobiphenyl was found not to be irritant to the rabbit skin or eye. The oral and dermal LD 50' in the rat are greater than 5 g/kg. In a 90 days feeding trial in rats no toxic effect were demonstrated at the levels of 100 and 500 ppm. However, hepatic change occured with diet containing 2.000 ppm. In a 4 weeks dust inhalation study, the no effect level was between 0.005 and 0.05 mg/l of air. The higher concentrations induced hepatic changes. Decabromobiphenyl was not teratogenic or embryotoxic to the rat at 10, 100 and 1.000 mg/kg per os. There was no evidence to indicate that the compound has mutagenic potential. Comparing the toxicological profile of decabromobiphenyl with other polybrominated biphenyl flame retardants would indicate that the toxicity decreases when the number of bromine atoms is increased.
The physiological onset and establishment of adult pituitary-testicular function has been characterised for Beagle dogs. Testicular measurements, circulating prolactin, luteinising hormone and testosterone concentrations, semen analyses and the histological appearance of testicular biopsies, suggest that male Beagles attain sexual maturity between 35 and 41 weeks of age. The assessment of testicular toxicity is discussed and attention drawn to possible approaches for investigating primary mechanisms of toxic action on the canine testis. Expected values for testicular size, hormone levels and semen characteristics are reported.